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Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity.

Neuron | Feb 19, 2004

http://www.ncbi.nlm.nih.gov/pubmed/14980210

To identify the molecular mechanisms underlying psychostimulant-elicited plasticity in the brain reward system, we undertook a phenotype-driven approach using genome-wide microarray profiling of striatal transcripts from three genetic and one pharmacological mouse models of psychostimulant or dopamine supersensitivity. A small set of co-affected genes was identified. One of these genes encoding the synaptic scaffolding protein PSD-95 is downregulated in the striatum of all three mutants and in chronically, but not acutely, cocaine-treated mice. At the synaptic level, enhanced long-term potentiation (LTP) of the frontocortico-accumbal glutamatergic synapses correlates with PSD-95 reduction in every case. Finally, targeted deletion of PSD-95 in an independent line of mice enhances LTP, augments the acute locomotor-stimulating effects of cocaine, but leads to no further behavioral plasticity in response to chronic cocaine. Our findings uncover a previously unappreciated role of PSD-95 in psychostimulant action and identify a molecular and cellular mechanism shared between drug-related plasticity and learning.

Pubmed ID: 14980210 RIS Download

Mesh terms: Animals | Behavior, Animal | Brain | Cocaine | Cocaine-Related Disorders | Dopamine | Down-Regulation | Guanylate Kinase | In Vitro Techniques | Intracellular Signaling Peptides and Proteins | Long-Term Potentiation | Membrane Proteins | Mice | Mice, Inbred C57BL | Mice, Knockout | Motor Activity | Nerve Tissue Proteins | Neural Pathways | Neuronal Plasticity | Nucleus Accumbens | Presynaptic Terminals | RNA, Messenger | Reward | Synaptic Transmission

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Associated grants

  • Agency: NIDA NIH HHS, Id: DA13511

Mouse Genome Informatics (Data, Gene Annotation)

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